Polyene intermediates and methods of making same



Patented Mar. 16, 1954 UNITED STATES PATENT OFFICE 2,672,481 I OLYE'N'E INTERMEDIATEs D METHODS OF MAKING SAME Leonard Weisler and John M.- Di eterle; Rochester, N. Y., assignors to EastmanKodak Company,- Roohester, N. Y., a corporation of New Jersey No brewing. Amplification November 25', 1950,

serial No. 197,642

7 Claims;

This invention relates to chemical intermedi= ates useful in the synthesis of polyenes and to methods of making such intermediates.

The synthesis of poiyenes such as vitamin A and similar caroteneid polyenes is complicated by the tendency of the materials to isomeric; under reaction conditions give a mixture of the desired aB-uiisatiirated compound and an uiidesir'able fi unsaturated isomer of the desired compound The objectionable isoineiization oi Delyenes during synthesis, and particularly during dehydration of a hydroii'y compound; is large'-' 1y oviated by the use or an intermediate having an acetylenic linkage in the carbon chain to limit the dehydration to s desired position.

It is aeeordingly an object oi this invention to 'priiidd a 116W and useful inethd of making a compound which is enable of entering into poiyens syntheses without objectionable isomerization.

It is also an object of this inventiontd provide an improved method of makin intermediates useful in the synthesis of vitamin A A further object or this invention is to pro= videan improved method of making a deriv'a tive of trimethm cyclohexanone having: a side chain containing acetylenic linkage.

Another object of th invention is to provide an improved method of making 1-(2,6,6'-tri-' methyl cyclohexen l yl) but-1-yne-3 one;

Another object of the invention is to provide new compound which are convertible to 142,6,6- trimethyl oyclohexen l-yh but-i-yne s onei Anethei object or the invention is to facilitate the synthesis of vitamin A by providing new methds of synthesizin im roved vitamin A in terms-dimes Qther objects will be apparent from the description and claims which follow.

These and ether objects are attained by means of thisinvention which comprises converting trimsthyi cyclohexanone to l-(2,6,6-trimethyl cyclohexen r-yl) but 'l-yne' fl-one by condensing 2,6,6-=trimethyl cy'clohexahone with but-1-'yne-'3= olto term the condensation product, l-"(l-hy droxy lfi'fi-trimeth-yl cyclohexane) but=1-yn'e-3'- 01,. oxidizing this condensation product to the oxidation product,- l-(l-hydroxy-2,6,6-trimethyl cyclohexane) but-1 yne-3-one, and dehydrating this oxidation product to l-(2,6,6-trimethyl yclohexen-l-yl) but-1-yne-3-one.

The condensation of the 2,6,6-trimethyl cy clohe-xanone with the but-1yne3-o1. is carried out in the presence of a suitable condensation catalyst such as lithium amide, sodamide, potassium amide, calcium amide, a Grignard reagent, or a catalyst complex of potassium hydroxide and a solvent having two ether-oxygen ato'ms separated by one or two carbon atoms,- such as acetals, ketals or dialkyl ethers of ethyl"- ene glycols, as for example acetaldehyde di ropyl acetal, as prepared by the method of Weiz= mann set out in U. 8-. Patent 2,472,135. The con'-" densation is desirably effected in liquid ammonia at lowered temperatures for ready control of the reaction;

The product of the condensing, l -(lhydroxy 2,6,6-trimethyl cycloheiiane) but'-1-=yne -3=0l, is then oxidized to the corresponding ketone, 1-(1--= hydroxy 2,6,6 trimethyl cyclohexane) but s l yne 3-cne' by one of the oxidation procedures suitable for converting carbinols to earbon'yls as for example by subjecting the condensation prod= uct to the Oppen'auer procedure employing a magnesium alkoxide or an aluminum alkox-ide as oxidizing agent or by treating the condensa= tion product with an oxidizing inorganic oxide; Thus suitable oxidizing agents include aluminuni isopropoxide, aluminum t-butoxide, manganese dioxide, magnesium isofii oijiiide, chromic oxide, magnesium ethos-ids and similar wsll known oi:- idizing agents.- The oxidation proceeds readily at room temperature in some cases,- although elevated temperatures can be emplo ed if de siredfor accelerating the course of the oxidation. The oxidation is desirably efie'cted solvent thedi-um, With inert hydrocarbon solvents as benzene, hexane, or the like being asirabl-y fii i ioys'd. such sass, the oxidation is desirably effected by refluxing the reaction mixture,

The hydroizy lie't'o'ne terri ied as oxidation prod-= not is then dehydrated to remove the hydroiiylgroupsubstitunt on the ring and thereby can: vert the hydroxy ketone to the desired 1'-(2;6,6-* tri-inethyl oydon xe'ri-i yi) but-l ns- 3 one. Dehydration is effected by treatin the nydroxy ketone with an acidic dehydrating agent. Thus dehydration is elicited by distilling the hydroxy ketone from fused sodium acid sulfate, by treating it with thionyi cl-i-l'ride in pyrid ne at 16W teiiiberatiire such as 20" 0., by tfating it a mixture of acetic acid and acetic anhydi-id cataly'fied with ethyl hydrogen Sulfate,- by treat in it with sulfuric acid, or by treating it with other acidic materials in accordance with known dehydration practices.-

The resulting 1-(2,6,6-trimethy1 cyclohexen- 1-y1) but-l-yne-S-one obtained by means or the process embodying this invention can thereafter be used in the synthesis of polyenes of the caret enoid series.

The invention is illustrated by reference to certain preferred embodiments thereof as detailed in the following examples.

Example 1 The condensation of 2,6,6-trimethyl cyclohexanone with but-1-yne-3-ol is effected in excellent yield in accordance with the following procedure. A 22 g. portion of lithium amide was added to 500 ml. of liquid ammonia. This mixture was maintained at 'T0 C. and stirred while 26 g. of but-1-yne-3-one was added over a period of 30 minutes. The mixture was allowed to stand for an additional 30 minutes, aftor which time, a dropwise addition of 45 g. of 2,6,6-trimethyl cyclohexanone was effected at the rate of 1 g. per minute, followed by the addition of 50 ml. of dry ether. The temperature of the reaction mixture was permitted to rise to 40 C. and then the mixture was maintained at that temperature for hours. The ammonia was allowed to evaporate from the reaction mixture and gradually replaced with 400 ml. of dry ether. The reaction mixture was allowed to stand overnight at room temperature. The mixture was then cooled to 5 C. and 250 ml. of saturated ammonium chloride added thereto. The ether layer was separated from the aqueous layer, and the aqueous layer extracted with ether. The combined ether solutions were then washed with dilute hydrochloric acid and saturated sodium chloride solution, dried, and the ether removed by distillation. Unreacted trimethyl cyclohexanone and but-1- yne-3-ol were distilled away leaving 36 g. of 1- (1-hydroxy-2,6,6-trimethyl cyclohexane) but-1- yne-3-ol as a viscous orange oil. Similar results, although in somewhat lowered yields, are obtained with other well-known condensation catalysts such as sodamide, Weizmann catalyst, calcium amide and potassium amide, or by the Grignard procedure.

Example 2 The oxidation of 1-(1-hydroxy-2,6,6-trimethyl cyclohexane) but-1yne-3-ol to the corresponding hydroxy ketone, 1-(1-hydroxy-2,6,6- trimethyl oyclohexane) but-l-yne-S-one, proceeds readily by means of the Oppenauer oxidation procedure with metal alkoxides such as aluminum or magnesium alkoxides as well as with oxidizing inorganic oxides. Thus, for example, the oxidation with manganese dioxide was carried out as follows. Thirty-six grams of 1-(1-hydroxy-2,6,6-trimethyl eyclohexane) but-1-yne-3-ol were dissolved in 300 ml. of hexane and a 200 g. portion of precipitated. manganese dioxide was added. The mixture was stirred and refluxed for 90 minutes and then filtered. The product weighed 34.5 g. and

had

Upon vacuum distillation, 24.7 g. of l-(l-hydroxy-2,6,6-trimethyl cyclohexane) but-l-yne- 3-one was obtained having a boiling point at '7 mm. Hg pressure of 146-147 C. and having E23,, (225 my.) =323 Example 3 The hydroxy ketone, 1-(l-hydroxy-2,6,6-trimethyl cyclohexane) but-l-yne-3-one is dehydrated to the desired 1-(2,6,6-trimethyl cyclohexen-1-y1) but-l-yne-3-one by treatment with an acid dehydrating agent. In a typical case, a 2.0 g. portion of the hydroxy ketone was dis- 4, tilled under reduced pressure from fused sodium bisulfate. The product concentrate of 1- (2,6,6-trimethyl cyclohexen-l-yl) but-1-yne-3- one boiled at 137 C. under 13 mm. pressure and had l a... u)=262 It gave a 2,4-dinitrophenyl hydrazone derivative which melted at 137-139" C. uncorrected and had E11,, (372 my) =690 Other typical dehydration procedures include treating the hydroxy ketone with thionyl chloride and pyridine at -20 C., or treating it with a mixture of acetic acid and acetic anhydride containing a small amount of ethyl hydrogen sulfate. If desired, the ketonic group can be protected during dehydration by ketalization in accordance with known practices whereupon the product is hydrolyzed following dehydration to reconstitute the ketone. Ketalization is effective also in case it is desired to convert the but- 1-yne-3-ol to the corresponding ketone before condensation.

This invention thus provides a new and improved method of making chemical intermediates which are useful in polyene syntheses and particularly in making 1-(2,6,6-trimethyl cyclohexen-l-yl) but-1-yne-3-one which is capable of entering into vitamin A syntheses without objectionable isomerization.

While the invention has been described in considerable detail with reference to certain preferred embodiments, it will be understood that variations and modifications can be effected without departing from the spirit and scope of the invention as described hereinabove and as defined in the appended claims.

We claim:

1. The method of making a compound capable of entering into polyene syntheses without isomerization which comprises condensing 2,6,6- trimethyl cyclohexanone with but-1-yne-3-ol in the presence of a condensation catalyst and thereby forming 1-(1-hydroXy-2,6,6-trimethyl cyclohexane)-but-1-yne-3-ol as condensation product, oxidizing said condensation product with a metal-containing oxidizing agent and thereby forming the oxidation product l-(l-hydroxy-2,6,6-trimethyl cyclohexane)-but-1-yne- S-one, and dehydrating said oxidation product with an acidic dehydrating agent and thereby converting said oxidation product to 1-(2,6,6-

trimethyl cyclohexen-l-yl) -but-1-yne-3-one.

2. The method of making a compound capable of entering into polyene syntheses without isomerization which comprises condensing 2,6,6- trimethyl cyclohexanone with but-1-yne-3-ol in the presence of a condensation catalyst and thereby forming 1-(1-hydroxy-2,6,6-trimethyl cyclohexane) but-l-yne-3-ol as condensation product, oxidizing said condensation product with an oxidizing agent selected from the class consisting of magnesium alkoxides, aluminum alkoxides, manganese dioxide and chromic oxide and thereby forming 1-(1-hydroxy-2,6,6-trimethyl cyclohexane) but-1-yne-3-one as oxidation product, and dehydrating said oxidation product with an acidic dehydrating agent and thereby converting said oxidation product to 1-(2,6,6-trimethyl oyclohexen-l-yl) but-1-yne 3-one.

3. The method of making a compound capable of entering into polyene syntheses without isomerization which comprises condensing 2,6,6- trimethyl cyclohexanone with but-1-yne-3-ol in liquid ammonia and in the presence of lithium amide and thereby forming 1-(1-hydroxy-2,6,6 trimethyl-cyclohexane) but-1-yne-3-ol as condensation product, oxidizing said condensation product with a metal-containing oxidizing agent and thereby forming 1-(1-hydroxy-2,6,6-trimethyl-cyclohexane) but-1-yne-3-one as oxidation product, and dehydrating said oxidation product to 1-(2,6,6-trimethy1 cyclohexen-l-yl) but-1-yne-3-one with an acidic dehydrating agent.

4. The method of making a compound capable of entering into polyene syntheses without isomerization which comprises condensing 2,6,6- trimethyl cyclohexanone with but-1-yne-3-o1 in the presence of a metal amide condensation catalyst and thereby forming l-(l-hydroxy- 2,6,6-trimethyl cyclohexane) but-1-yne-3-ol as condensation product, oxidizing said condensation product with an oxidizing agent selected from the class consisting of magnesium alkoxides, aluminum alkoxides, manganese dioxide and chromic oxide and thereby forming 1-(1- hydroxy 2,6,6 trimethyl cyclohexane) but-1- yne-B-one as oxidation product, and treating said oxidation product with an acidic dehydrating agent and thereby dehydrating said oxidation product to 1-(2,6,6-trimethy1 cyclohexene-l-yl) but-l-yne-B-one.

5. The method of making a compound capable of entering into polyene syntheses without isomerization which comprises condensing 2,6,6-trimethyl cyclohexanone with but-1-yne-3- 01 in liquid ammonia and in the presence of lithium amide and thereby forming 1-(1-hydroxy-2,6,6-trimethyl cyclohexane) but-1-yne-3- 01 as condensation product, oxidizing said condensation product with an oxidizing agent selected from the class consisting of magnesium alkoxides, aluminum alkoxides, manganese dioxide and chromic oxide and thereby forming 1-(1-hydroxy-2,6,6-trimethyl cyclohexane) but- 1-yne-3-one as oxidation product, and thereafter treating said oxidation product with an acidic dehydrating agent and thereby dehydrating said oxidation product to 1-(2,6,6-trimethy1cyc1ohexen-l-yl) but-1-yne-3-one.

6. As a new chemical compound, l-(l-hydroxy- 2,6,6-trimethyl cyclohexane) but-1-yne-3-ol.

'7. As a new chemical compound, 1-(1-hydroxy- 2,6,6-trimethyl cyclohexane) but-1-yne-3-one.

LEONARD WEISLER. JOHN M. DIETERLE.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,531,567 Heilbron et al. Nov. 28, 1950 FOREIGN PATENTS Number Country Date 627,453 Great Britain Aug. 9, 1949 OTHER REFERENCES Ball et al.: Biochemical Journal, vol. 42, pages 516-523 (1948) Milas et al.: J. Am. Chem. Soc., vol. 70, pages 1597-1607 (1948).

Milas et al.: J. Am. Chem. Soc., vol. 70, pages 1829-1834 (1948).

Isler: Chimia, vol. 4, pages 103-118, May 1950. 

1. THE METHOD OF MAKING A COMPOUND CAPABLE OF ENTERING INTO POLYENE SYNTHESES WITHOUT ISOMERIZATION WHICH COMPRISES CONDENSING 2,6,6TRIMETHYL CYCLOHEXANONE WITH BUT-1-YNE-3-OL IN THE PRESENCE OF A CONDENSATION CATALYST AND THEREBY FORMING 1-(1-HYDROXY-2,6,6-TRIMETHYL CYCLOHEXANE) -BUT-1-YNE-3-OL AS CONDENSATION PRODUCT, OXIDIZING SAID CONDENSATION PRODUCT WITH A METAL-CONTAINING OXIDIZING AGENT AND THEREBY FORMING THE OXIDATION PRODUCT 1-(1-HYDROXY-2,6,6-TRIMETHYL CYCLOHEXANE) -BUT-1-YNE3-ONE, AND DEHYDRATING SAID OXIDATION PRODUCT WITH AN ACIDIC DEHYDRATING AGENT AND THEREBY CONVERTING SAID OXIDATION PRODUCT TO 1-(2,6,6TRIMETHYL CYCLOHEXEN-1-YL) -BUT-1-YNE-3ONE. 